miR-27 is associated with chemoresistance in esophageal cancer through transformation of normal fibroblasts to cancer-associated fibroblasts

There is increasing evidence that the expression of microRNA (miRNA) in cancer is associated with chemosensitivity but the mechanism of miRNA-induced chemoresistance has not been fully elucidated. The aim of this study was to examine the role of extracellular miRNA in the response to chemotherapy in esophageal cancer. First, serum expression of miRNAs selected by miRNA array was measured by quantitative reverse transcription-polymerase chain reaction in 68 patients with esophageal cancer who received cisplatin-based chemotherapy to examine the relationship between miRNA expression and response to chemotherapy. The serum expression levels of 18 miRNAs were different between responders and non-responders by miRNA array. Of these, high expression levels of miR-27a/b correlated with poor response to chemotherapy in patients with esophageal cancer. Next, in vitro assays were conducted to investigate the mechanism of miRNA-induced chemoresistance. Although transfection of miR-27a/b to cancer cells had no significant impact on chemosensitivity, esophageal cancer cells cultured in supernatant of miR-27a/b-transfected normal fibroblast showed reduced chemosensitivity to cisplatin, compared with cancer cells cultured in supernatant of normal fibroblast. MiR-27a/b-transfected normal fibroblast showed alpha-smooth muscle actin (alpha-SMA) expression, a marker of cancer-associated fibroblasts (CAF) and increased production of transforming growth factor-beta (TGF-beta). Chemosensitivity recovered after administration of neutralizing antibody of TGF-beta to the supernatant transfer experiments. Our results indicated that miR-27a/b is involved in resistance to chemotherapy in esophageal cancer, through miR-27a/b-induced transformation of normal fibroblast into CAF.